A δ-cell subpopulation with a pro-β-cell identity contributes to efficient age-independent recovery in a zebrafish model of diabetes.

Abstract

Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new <i>Insulin</i>-expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new <i>in</i>s<i>ulin</i> cells differ from the original β-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to β-cell destruction is fast, efficient, and age-independent. Bihormonal cells are transcriptionally close to a subset of δ-cells that we identified in control islets and that are characterized by the expression of <i>somatostatin 1.1</i> (<i>sst1.1</i>) and by genes essential for glucose-induced Insulin secretion in β-cells such as <i>pdx1</i>, s<i>lc2a2</i> and <i>gck</i>. We observed in vivo the conversion of monohormonal <i>sst1.1-</i>expressing cells to <i>sst1.1+ ins</i> + bihormonal cells following β-cell destruction. Our findings support the conclusion that <i>sst1.1</i> δ-cells possess a pro-β identity enabling them to contribute to the neogenesis of Insulin-producing cells during regeneration. This work unveils that abundant and functional bihormonal cells benefit to diabetes recovery in zebrafish.